Background-Upregulation of Th1 associated intrahepatic cytokines in chronic hepatitis C virus (HCV) infection should lead to a significant non-specific cellular immune response, a prerequisite for viral clearance. However, to date, the role of this non-specific response in HCV has been understudied. Aims-To analyse the intrahepatic macrophage activity in chronic HCV infection by immunostaining and by quantitation of cytokine mRNA. Methods-HCV positive liver tissues (chronic hepatitis, n=10; cirrhosis, n=5) were immunostained for CD68, MAC387, and semiquantitated by polymerase chain reaction for intrahepatic cytokine mRNAs (interferon (IFN ), interleukin 1 (IL-1 ), IL-6, IL-18, tumour necrosis factor (TNF ), and macrophage inflammatory protein 1 (MIP1 )). HCV negative normal liver tissues (for cytokines, n=6; for immunostaining, n=5) were included as controls.
Results-MAC387+ cells were focally increased in areas of erosion at the limiting plate while lobular staining was minimal. CD68 + staining was diVuse in both portal (increased in HCV) and lobular areas. The portal tract (mean) density of CD68 + and MAC387 + cells was significantly increased in patients with HCV compared with normal tissue. IFN and IL-18 mRNA levels were highly correlated and significantly upregulated in chronic hepatitis and cirrhotic tissue versus controls. TNF mRNA was upregulated in chronic hepatitis without cirrhosis, while IL-6 mRNA was significantly downregulated. IL-1 , IL-6, and MIP1 mRNA levels were significantly correlated with portal tract MAC387 + cell density. Conclusions-The significant upregulation of IFN and IL-18 mRNA and significant correlations between IFN and other proinflammatory cytokines, suggest a Th1/cell mediated intrahepatic immune response in chronic HCV infection. However, further clarification of the cellular sources of these cytokines is required. (Gut 2000;46:260-269)